Laboratory of Neuronal Communication

Legend The figure on top is a diagram of a presynaptic terminal contacting a post synaptic cell. Synaptic vesicles (yellow or blue) filled with transmitters fuse with the membrane and release neurotransmitters. Neurons can maintain release by various mechanisms including vesicle recycling (kiss-and-run or clathrin-mediated endocytosis) and recruitment of special vesicles located in a reserve pool (yellow). The second image from the top shows synaptic contacts of the Drosophila neuromuscular junction, a model synapse to study mechanisms of synaptic development and synaptic function. Synaptic contacts are labeled with different synaptic markers (Synaptotagmin in blue, DLG/PDZ-95 in green and Syndapin in red). The third image from the top depicts part of the adult Drosophila visual system, the lamina. In this synapse rich area individual photoreceptors are carefully sorted into individual units that transmit information to higher brain centres. Photoreceptor membranes are labeled in red (anti-chaoptin) and synaptic terminals are labeled in green (anti-endophilin). This image appeared on the cover of J. Neurosci (23:33) and was prepared with Robin Hiesinger. The bottom photo shows soap bubbles being blown from a wand, similar to synaptic vesicles that form and are pinched off the presynaptic membrane. This image appeared on the cover of Neuron (43:2) and was prepared with Nancy Van Driessche.

Group Leader: Patrik Verstreken

Members

Postdoctoral researcher: Ron Habets, Katarzyna Miskiewicz, Sven Vilain, Elsa Lauwers, Giovanni Esposito
Ph.D students: Dominik Haddad, Jarek Kasprowicz, Thang Khuong, Valerie Uytterhoeven, Melissa Vos, Jan Slabbaert, Liya Elsa Jose
Technical staff: Sabine Kuenen, Jef Swerts, Onno Schaap
Administrative staff: Tine Pellens

Research interests

In the laboratory of neuronal communication we aim to understand the molecular mechanisms of neurotransmission at live synapses. Such studies will eventually allow us to elucidate how alterations in transmitter release control complex behaviours, ultimately directing how our brain operates. Neurons talk to one another using small transmitter filled synaptic vesicles that fuse with the neuron membrane to release neurotransmitters activating the next cell in line. During intense stimulation, many vesicles are used and to ensure reliable communication, neurons massively recycle vesicles at their synaptic endings.
In the laboratory of neuronal communication we will address key aspects of neuronal function. For example, we are assessing the role of lipids in synaptic vesicle recycling and we are studying how synaptic mitochondria affect transmitter release in normal and diseased synapses. We are also performing genetic screens to identify novel components involved in vesicle recycling and neurological disease such as Parkinson’s. Given that altered synaptic communication is thought to be one of the leading causes of several deleterious neurological and psychiatric disorders, our studies will have significant implications for human mental health.

To study the molecular mechanisms of synaptic function in vivo, we are using a genetic approach using fruit flies as a model, screening for mutations in critical genes and revealing their function by studying mutant phenotypes. Flies are well suited to study the mechanisms underlying synaptic function since all key synaptic proteins identified in humans also exist in flies, and they show on average 75% protein similarity to their mammalian counterparts. Given the experimental advantages, flies are an ideal system to study vesicle recycling. In particular, we use the larval neuromuscular junction to combine Drosophila genetics with electrophysiology, electron microscopy, immunohistochemistry, calcium imaging, live dye uptake and release studies, and pharmacological inhibition of synaptic processes. In addition, we are implementing novel technologically advanced imaging techniques to study the mechanisms of synaptic plasticity. The ability to apply these assays to one single synapse is unique and very powerful, allowing us to propose very specific functions for the proteins studied.

Key Publications

• Morais VA, Verstreken P^, Röthig A, Smet J, Snellinx A, Haddad DM, Mandemakers W, Van Coster R, Wurst W, Scorrano L and De Strooper B^. Parkinson’s disease mutations in PINK1 affect Complex I activity in mitochondria. EMBO Molecular Medicine, In Press, 2008.
• Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK, van Vught PWJ, Landers JE, Sapp P, Van Den Bosch L, Knight J, Neale BM, Turner MR, Veldink JH, Ophoff RA, Tripathi1 VB, Beleza A, Shah MN, Proitsi P, Van Hoecke A, Carmeliet P, Horvitz HR, Leigh PN, Shaw CE, van den Berg LH, Sham PC, Powell JF, Verstreken P, Brown Jr RH., Robberecht W, Al-Chalabi A. Variants of the RNA polymerase II component ELP3 are associated with motor neuron degeneration. Human and Molecular Genetics, 18: 472-481, 2008.
• Kasprowicz J*, Kuenen S*, Habets R, Miskiewicz K, Smitz L and Verstreken.P. Inactivation of clathrin heavy chain inhibits synaptic recycling but allows bulk membrane uptake. The Journal of Cell Biology, 182:1007-1016, 2008.
• Venken KJT*, Kasprowicz J*, Kuenen S, Yan J, Hassan B and Verstreken P. Recombineering-mediated tagging of Drosophila genomic constructs for in vivo localization and acute protein inactivation. Nucleic Acids Research, DOI:10.1093/nar/gkn486, 2008.
• Romero E, Cha G-H, Verstreken P, Ly CV, Hughes RE, Bellen HJ, Botas J. Suppression of Neurodegeneration and Increased Neurotransmission Caused by Expanded Full-Length Huntingtin Accumulating in the Cytoplasm. Neuron, 57: 27-40, 2008.
• Ohyama T, Verstreken P, Ly CV, Rosenmund T, Rajan A, Tsien AC, Haueter C, Schulze KL, Bellen HJ. Huntingtin-interacting protein 14, a palmitoyl transferase required for exocytosis and targeting of CSP to synaptic vesicles. The Journal of Cell Biology 179:1481-1496, 2007.
• Ly CV, Verstreken P. Mitochondria at the synapse. The Neuroscientist, 12:291-299, 2006.
• Verstreken P, Ly CV, Venken KJT, Koh T-W, Zhou Y, Bellen HJ.Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47, 365-378, 2005
• Verstreken P, Koh T-W, Schulze KL, Zhai RG, Hiesinger PR, Zhou Y, Mehta SQ, Cao Y, Roos J, Bellen HJ. Synaptojanin is recruited by Endophilin to promote synaptic vesicle uncoating. Neuron 40, 733-748, 2003
• Verstreken P, Kjærulff O, Lloyd TE, Atkinson R, Zhou Y, Meinertzhagen IA, Bellen, HJ.Endophilin mutations block clathrin-mediated endocytosis but not neurotransmitter release. Cell 109, 101-112, 2002

Positions Available
PhD and Post Doc positions available: If you are interested to join a motivated and interactive group of researchers interested in neuronal communication, please contact us by email [patrik.verstreken@med.kuleuven.be] or telephone [+32 (16) 330018].